S-6-Fluorospiro[chroman-4,4'-imidazolidine]-2',5'-dione, also named S-2,3-dihydro-6-fluorospiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dion e (U.S.A.N.: sorbinil) of the formula ##STR1## is a highly potent aldose reductase inhibitor having especial value in effectively controlling the chronic complications of diabetes mellitus. (Sarges, U.S. Pat. No. 4,130,714). The present invention concerns an improved process for preparing sorbinil and intermediates used in this improved process.
Heretofore, sorbinil was prepared by resolution of the corresponding racemic 6-fluorospiro[chroman-4,4'-imidazolidine]-2',5'-dione, of the formula ##STR2## by using highly toxic brucine as the resolving agent in high volumes of solvent (U.S. Pat. No. 4,130,714).
Surprisingly, we have found that resolution of precursor 6-fluoro-4-ureidochroman-4-carboxylic acid, of the formula ##STR3## as either the D-(+)-(1-phenethyl)amine or the L-(-)-ephedrine salt, followed by simple cyclization in glacial acetic acid, provides an improved method for sorbinil. The racemic precursor is conveniently derived from the above racemic imidazolidine of the formula (II) via the amino acid of the formula ##STR4## In this manner, outstanding yields of sorbinil are obtained with much lower solvent volumes and with readily available, relatively inexpensive optically active amines. At the same time the use of a highly toxic resolving agent is avoided. The efficiency of this process is further enhanced by isolating the undesired enantiomer from mother liquors and recycling to fresh racemate, via precursor 6-fluoro-4-chromanone.
Sorbinil has also been more recently prepared by an alternative synthesis in which the required chirality is induced during the synthetic sequence (Sarges, U.S. Pat. No. 4,286,098).